Current acute treatments for the severely head-injured patient are focused on management of increased intracranial pressure (ICP) as a result of edema. Malignant ICP is a strong indicator for poor outcome, and its treatment is one of the most effective means of reducing mortality and morbidity (Ghajar, 2000; Treggiari et al., 2007). Treatment strategies for reducing ICP generally focus on the use of osmotic agents such as mannitol (Rangel-Castilla et al., 2008) or more recently hypertonic saline (Kerwin et al., 2009). The efficacy of mannitol however has been called into question recently (Wakai et al., 2007).
The search for new therapeutic targets continues with much attention devoted to two main areas: aquaporin channels and breakdown of the blood brain barrier (BBB) (Amorini et al., 2003; Vink and van den Heuvel, 2010; Zador et al., 2007). These components of the central nervous system represent major routes of entry for water into the brain during edema and act as facilitators to brain tissue swelling. One of the main drivers of brain tissue swelling is the fixed negative charge within brain cells that draws water into the brain following injury according to the Donnan effect (Elkin et al., 2010b).
The Donnan effect describes the tendency for a hydrated material comprised of charged molecules to generate an osmotic gradient of ions between its interstitium and the bathing solution due to the material's affinity for soluble and oppositely charged ions. This osmotic gradient produces a Donnan osmotic pressure, p, according to the following equation (Overbeek, 1956):p=RT(√{square root over ((cF)2+( c{square root over ( c*)2)}− c*)   (1)where R is the ideal gas constant, is absolute temperature, c* is the bath osmolarity, and cF is the concentration of the charged molecules fixed within the material known as the fixed charge density (FCD). The Donnan osmotic pressure will increase if the FCD increases or if the bath osmolarity decreases. Due to the osmotic pressure difference, water may be drawn into the material until the interstitial fluid pressure is balanced by tension in the solid matrix (due to its expansion) according to triphasic mixture material principles (Lai et al., 1991).
Negative charges on cytoplasmic constituents affect the ion balance between cells and the extracellular fluid (ECF) based on the Donnan effect (Kurbel, 2008). The homeostatic state requires both electroneutrality (with a negative membrane potential) and osmotic balance. This balance is maintained by multiple ion channels and pumps in the cell membrane, including the ATP-dependent Na+/K+ pump. Following injury, metabolic disruption compromises this homeostasis, resulting in exposure of the FCD to the ECF and an increase of the Donnan osmotic pressure inside cells. As ions enter cells, Donnan-mediated cellular swelling occurs, leading to the progression of edema as described in FIG. 1 and described in more detail in the discussion.